No abstract

Diarylpyrimidine derivatives (DAPYs) exhibit robust anti-HIV-1 potency, although they have been compromised by E138K variant and severe side-effects and been suffering from poor water solubility. In the present work, hydrophilic morpholine or methylsulfonyl and sulfamide-substituted piperazine/piperidines were introduced into the right wing of DAPYs targeting the solvent-exposed tolerant region I. The anti-HIV-1 activities of 11c (EC 50(WT) = 0.0035 μM, EC 50(E138K) = 0.0075 μM) were the same as and 2-fold better than that of the lead etravirine against the wild-type and E138K mutant HIV-1, respectively, with a relative low cytotoxicity (CC 50 ≥ 173 μM). Further test showed a significant improvement in the water solubility of 11c. Besides, 11c displayed no significant inhibition on main cytochrome P450 enzymes and exhibited no acute/ subacute toxicities at doses of 2000 mg•kg −1 /50 mg•kg −1 in mice. Taken together, we consider that 11c is a promising lead for further structural optimization.

Novel phenylalanine derivatives were discovered as HIV-1 capsid protein inhibitors via “click reaction”. Most of them exhibited remarkable anti-HIV-1 activity.

Solvent‐exposed regions, or solvent‐filled pockets, within or adjacent to the ligand‐binding sites of drug‐target proteins provide opportunities for substantial modifications of existing small‐molecular drug molecules without serious loss of activity. In this review, we present recent selected examples of exploitation of solvent‐exposed regions of proteins in drug design and development from the recent medicinal‐chemistry literature.

Currently, HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) are a major component of the highly active anti-retroviral therapy (HAART) regimen. However, the occurrence of drug-resistant strains and adverse reactions after long-term usage have inevitably compromised the clinical application of NNRTIs. Therefore, the development of novel inhibitors with distinct anti-resistance profiles and better pharmacological properties is still an enormous challenge. Herein, we summarize state-of-the-art medicinal chemistry strategies for the discovery of potent NNRTIs, such as structure-based design strategies, contemporary computer-aided drug design, covalent-binding strategies, and the application of multi-target-directed ligands. The strategies described here will facilitate the identification of promising HIV-1 NNRTIs.

No abstract

Enlightened by the available structural biology information, a novel series of dihydrothiopyrano­[4,3-d]­pyrimidine derivatives were rationally designed via scaffold hopping and molecular hybridization strategies. Notably, compound 20a yielded exceptionally potent antiviral activities (EC50 = 4.44–54.5 nM) against various HIV-1 strains and improved resistance profiles (RF = 0.5–5.6) compared to etravirine and rilpivirine. Meanwhile, 20a exhibited reduced cytotoxicity (CC50 = 284 μM) and higher SI values (SI = 5210–63992). Molecular dynamics simulations were performed to rationalize the distinct resistance profiles. Besides, 20a displayed better solubility (sol. = 12.8 μg/mL) and no significant inhibition of the main CYP enzymes. Furthermore, 20a was characterized for prominent metabolic stability and in vivo safety properties. Most importantly, the hERG inhibition profile of 20a (IC50 = 19.84 μM) was a remarkable improvement. Overall, 20a possesses huge potential to serve as a promising drug candidate due to its excellent potency, low toxicity, and favorable drug-like properties.

Two novel series of human immunodeficiency virus‐1 (HIV‐1) non‐nucleoside reverse transcriptase inhibitors (NNRTIs) bearing a thiophene[3,2‐d]pyrimidine scaffold and sulfonamide linker in the right wing have been identified, which demonstrated activity against the wild‐type (WT) HIV‐1 strain in MT‐4 cells with inhibitory concentrations ranging from micromolar to submicromolar. Especially, against the mutant strains K103N and E138K, most compounds exhibited more potent activity than against WT HIV‐1. Compound 7 (EC50 = 0.014, 0.031 μM) achieved the most potent activity against the two mutants, being more effective than that of nevirapine (NVP, EC50 = 7.572, 0.190 μM) and comparable to that of etravirine (ETV, EC50 = 0.004, 0.014 μM). Molecular docking experiments on the novel analogs have also suggested that the extensive network of main chain hydrogen bonds are important in the binding mode, which may provide valuable insights for further optimization.